GPRC5A promotes lung colonization of esophageal squamous cell carcinoma

Emerging evidence suggests that cancer cells may disseminate early, prior to the formation of traditional macro-metastases. However, the mechanisms underlying the seeding and transition of early disseminated cancer cells (DCCs) into metastatic tumors remain poorly understood. Through single-cell RNA sequencing, we show that early lung DCCs from esophageal squamous cell carcinoma (ESCC) exhibit a trophoblast-like ‘tumor implantation’ phenotype, which enhances their dissemination and supports metastatic growth. Notably, ESCC cells overexpressing GPRC5A demonstrate improved implantation and persistence, resulting in macro-metastases in the lungs. Clinically, elevated GPRC5A level is associated with poorer outcomes in a cohort of 148 ESCC patients. Mechanistically, GPRC5A is found to potentially interact with WWP1, facilitating the polyubiquitination and degradation of LATS1, thereby activating YAP1 signaling pathways essential for metastasis. Importantly, targeting YAP1 axis with CA3 or TED-347 significantly diminishes early implantation and macro-metastases. Thus, the GPRC5A/WWP1/LATS1/YAP1 pathway represents a crucial target for therapeutic intervention in ESCC lung metastases. The mechanisms allowing early disseminated cancer cells colonize other tissues remain largely unknown. Here, authors show that GPRC5A axis drives esophageal squamous cell carcinoma lung seeding and metastasis, in a mechanism resembling trophoblast behavior during embryo implantation.